Home About us Contact
|
Home About us Contact | ||
|
|
||
Pharmacodynamic Data (pharmacodynamic + data)
Selected AbstractsPharmacodynamics of Carvedilol in Conscious, Healthy DogsJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 2 2006Sonya G. Gordon The purpose of the study reported here was to determine the magnitude and duration of beta-blocking efficacy, determine an effective dose and dosing interval, and document safety and tolerability of carvedilol given orally in clinically normal dogs. Pharmacodynamic data were evaluated in conscious, unrestrained, healthy hound dogs at baseline and after long-term oral administration of carvedilol (1.5 mg/kg of body weight PO q12h for >5 days). At baseline, heart rate (HR) and blood pressure (BP) data were collected continuously for 24 hours, and complete echocardiography was performed. This protocol was repeated after long-term oral carvedilol administration. Additionally, isoproterenol was administered to evaluate the magnitude and duration of the nonselective beta-blocking efficacy of carvedilol. An isoproterenol challenge was performed 0.75, 1.5, 2.25, 4, 6, 12, and 24 hours after carvedilol administration, with echocardiography being performed once at 2 hours. Plasma samples were obtained prior to each challenge time point for determination of plasma carvedilol concentration. Time series regression analysis indicated no difference between baseline and carvedilol-induced HR or BP trend lines in 6 of 8 dogs. In 2 of 8 dogs, HR, after long-term carvedilol administration, was reduced. Carvedilol attenuated isoproterenol-induced changes in HR by 54,76% through 12 hours and by 30% at 24 hours. The BP changes were attenuated by 80,100% through 12 hours. These data suggest that carvedilol (1.5 mg/kg PO q12h) in healthy, conscious dogs confers nonselective beta blockade for 12 hours, with minimal effects on resting HR, BP, and echocardiographic variables. Additionally, the magnitude of beta blockade correlated strongly to peak plasma carvedilol concentration, suggesting that therapeutic drug monitoring may be clinically useful. [source] Lamotrigine pharmacokinetic/pharmacodynamic modelling in ratsFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 6 2005M.M. Castel-Branco Abstract The aim of this study was to perform a pharmacokinetic/pharmacodynamic (PK/PD) modelling of lamotrigine following its acute administration to rats. Adult male Wistar rats were given 10 mg/kg of lamotrigine intraperitoneally. Plasma and brain samples were obtained at predetermined times over 120 h post-dose and analysed by liquid chromatography. The anticonvulsant profile against maximal electroshock seizure stimulation was determined over 48 h after dosing. As a linear relationship between lamotrigine plasma and brain profiles was observed, only the plasma data set was used to establish the PK/PD relationship. To fit the effect,time course of lamotrigine, the PK/PD simultaneous fitting link model was used: the pharmacokinetic parameters and dosing information were used in the one-compartment first-order model to predict concentrations, which were then used to model the pharmacodynamic data with the sigmoid Emax model, in order to estimate all the parameters simultaneously. The following parameters were obtained: Vd = 2.00 L/kg, kabs = 8.50 h,1, kel = 0.025 h,1, ke0 = 3.75 h,1, Emax = 100.0% (fixed), EC50 = 3.44 mg/L and , = 8.64. From these results, it can be stated that lamotrigine is extensively distributed through the body, its plasma elimination half-life is around 28 h and a lamotrigine plasma concentration of 3.44 mg/L is enough to protect 50% of the animals. When compared with humans, the plasma concentrations achieved with this dose were within the therapeutic concentration range that had been proposed for epileptic patients. With the present PK/PD modelling it was possible to fit simultaneously the time-courses of the plasma levels and the anticonvulsant effect of lamotrigine, providing information not only about the pharmacokinetics of lamotrigine in the rat but also about its anticonvulsant response over time. As this approach can be easily applied to other drugs, it becomes a useful tool for an explanatory comparison between lamotrigine and other antiepileptic drugs. [source] Paclitaxel and cisplatin as intravesical agents against non-muscle-invasive bladder cancerBJU INTERNATIONAL, Issue 11 2008Boris A. Hadaschik OBJECTIVES To investigate the effects of cisplatin and paclitaxel against human bladder cancer cells in vitro, and to obtain both pharmacokinetic and pharmacodynamic data after intravesical administration in mice. MATERIALS AND METHODS Six bladder cancer cell lines (J82, KU7, RT4, SW780, T24, UMUC3) were treated with various combined doses of both drugs and cell proliferation was evaluated 3 days later. In vivo, solutions of cisplatin and micellar paclitaxel were instilled transurethrally in female mice and pharmacokinetic data were acquired using high-performance liquid chromatography-mass spectrometry and atomic absorption methods. To obtain efficacy data, mice with orthotopic KU7-luc tumours were administered cisplatin and/or micellar paclitaxel intravesically, and the tumour burden quantified using bioluminescence imaging. RESULTS In vitro, both cisplatin and paclitaxel potently decreased the proliferation of all cell lines tested, and in combination had an additive but not a synergistic effect. After intravesical instillation, mouse serum concentrations of cisplatin and paclitaxel were in the low microgram/millilitre range and bladder tissue concentrations achieved were 82 and 241 µg/g, respectively. Similar drug levels were reached using combined therapy. In vivo, all chemotherapeutic agents significantly inhibited bladder tumour growth, with the best results for combined therapy and micellar paclitaxel alone. However, there was toxicity in the combined treatment arm. CONCLUSIONS Both cisplatin and paclitaxel were absorbed at effective amounts into bladder tissues. As intravesical agents, paclitaxel had slightly stronger anticancer potency than cisplatin. Due to increased adverse events, caution should be exercised when combining both cisplatin and paclitaxel intravesically. [source] Structural and ligand-binding properties of serum albumin species interacting with a biomembrane interfaceJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 11 2007Takamitsu Kosa Abstract In the process of drug development, preclinical testing using experimental animals is an important aspect, for verification of the efficacy and safety of a drug. Serum albumin is a major binding protein for endogenous and exogenous ligands and regulates their distribution in various tissues. In this study, the structural and drug-binding properties of albumins on a biomembrane surface were investigated using reverse micelles as a model membrane. In reverse micelles, the secondary structures of all albumins were found, to varying degrees, to be intermediate between the native and denatured states. The tertiary structures of human and bovine albumin were similar to those of the native and intermediate states, respectively, whereas those of the dog, rabbit, and rat were in a denatured state. Thus, bovine albumin is an appropriate model for studying structural changes in human albumin in a membrane-water phase. Binding studies also showed the presence of species difference in the change in binding capacity of albumins during their interaction with reverse micelles. Among the albumins, rat albumin appears to be a good model for the protein-mediated drug uptake of human albumin in a biomembrane environment. These findings are significant in terms of the appropriate extrapolation of pharmacokinetics and pharmacodynamics data in various animals to humans. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 3117,3124, 2007 [source] | ||||||||||